Revisiting the roles of hepatic inflammation and adipokines in metabolic disease

Obesity is a major health problem, because it induces type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Hepatic inflammation and an altered secretion of adipokines (bioactive substances secreted by fat tissue) are believed to be involved in the pathogenesis of these diseases. In this thesis their role is further elucidated.

The role of hepatic inflammation in the development of T2D was studied in two mouse models with hepatic inflammation. It was investigated if these mice developed insulin resistance (IR, precedes T2D) faster than mice without hepatic inflammation. In both models, hepatic inflammation did not affect the development of IR. NAFLD is also associated with IR. In a review article it was shown that there is little evidence for a causal relationship. In most cases, the relationship was explained by alterations in body weight.

In addition, we investigated in patients if the presence of various adipokines in fat and liver tissue is correlated with NAFLD. Especially the adipokine chemerin was correlated with reduced disease severity. To investigate if chemerin actually protects against NAFLD, mice insensitive to chemerin and mice with increased chemerin levels were used. In both models, chemerin did not protect against the development of NAFLD.

From these results, we conclude that hepatic inflammation, in contrast to the current dogma, does not contribute to the pathogenesis of T2D. In addition, we conclude that chemerin does not protect against NAFLD. Therefore, this thesis raises the question whether medications directed against inflammation or chemerin will be effective against these diseases.